rs118177681

Variant names:

• chr15-33844930-G-A
• rs118177681
• NM_001036.6:c.13365G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001036.6(RYR3):​c.13365G>A​(p.Glu4455Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,996 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., cov: 33)
  • Exomes 𝑓: 0.011 (131 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.161
• Publications: 3 publications found

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RYR3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-33844930-G-A is Benign according to our data. Variant chr15-33844930-G-A is described in ClinVar as Benign. ClinVar VariationId is 461862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.161 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00882 (1343/152310) while in subpopulation SAS AF = 0.0253 (122/4824). AF 95% confidence interval is 0.0216. There are 11 homozygotes in GnomAd4. There are 671 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.13365G>A	p.Glu4455Glu	synonymous_variant	Exon 93 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.13365G>A	p.Glu4455Glu	synonymous_variant	Exon 93 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1344 AN: 152192 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.0113 AC: 2817 AN: 249270 AF XY: 0.0125

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00765

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00446

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0114 AC: 16596 AN: 1461686 Hom.: 131 Cov.: 34 AF XY: 0.0119 AC XY: 8637 AN XY: 727126

African (AFR) AF: 0.00170 AC: 57 AN: 33478

American (AMR) AF: 0.00787 AC: 352 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 596 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0241 AC: 2079 AN: 86256

European-Finnish (FIN) AF: 0.00498 AC: 266 AN: 53402

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12416 AN: 1111850

Other (OTH) AF: 0.0121 AC: 732 AN: 60372

GnomAD4 genome AF: 0.00882 AC: 1343 AN: 152310 Hom.: 11 Cov.: 33 AF XY: 0.00901 AC XY: 671 AN XY: 74476

African (AFR) AF: 0.00200 AC: 83 AN: 41564

American (AMR) AF: 0.00941 AC: 144 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0253 AC: 122 AN: 4824

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 838 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.0113 Hom.: 8

Bravo AF: 0.00830

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.69
DANN	Benign	0.68
PhyloP100		-0.16
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs118177681; hg19: chr15-34137131;